title: Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects.
abstract: OBJECTIVE
  The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor.
  
  
  METHODS
  This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed.
  
  
  RESULTS
  Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole).
  
  
  CONCLUSIONS
  Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.
authors.affiliation: Pfizer, Inc, Collegeville, Pennsylvania 19426, USA. abbasr@wyeth.com
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hug
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Jaime
authors.initials: J
authors.lastname: Burns
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D011804:Quinolines; C487932:neratinib; D007654:Ketoconazole